Droxidopa is a known synthetic amino acid precursor of norepinephrine that is converted directly to norepinephrine via the action of dopa decarboxylase (DDC). Droxidopa is generally used to treat orthostatic hypotension (OH) and can be categorized as an antiparkinsonian agent; however, multiple pharmacological activities have been observed with droxidopa, including the following: (1) it is directly converted to 1-norepinephrine by the action of the aromatic L-amino acid decarboxylase which is widely distributed in a living body, and thus has an effect of replenishing norepinephrine; (2) it has limited permeability through the blood-brain barrier into the brain; (3) it specifically recovers norepinephrine activated nerve functions which have decreased in the central and peripheral nervous system; and (4) it shows various actions, as norepinephrine, via the adrenaline receptors in various tissues.
Mood disorders form a category of mental health problems that include all types of depression and are sometimes called affective disorders. The most common types of mood disorders include: major depressive disorder, which is defined as an at least two-week period of a depressed or irritable mood or a noticeable decrease in interest or pleasure in usual activities, along with other signs of a mood disorder; dysthymia (dysthymic disorder), which is defined as a chronic, low-grade, depressed or irritable mood for at least one year; manic depression (bipolar disorder), which is defined as at least one episode of a depressed or irritable mood and at least one period of a manic (persistently elevated) mood; mood disorder due to a general medical condition (such as cancer, injuries, infections, and chronic medical illnesses), which can trigger symptoms of depression; and substance induced mood disorder, wherein symptoms of depression are present due to the effects of medication, drug abuse, exposure to toxins, or other forms of treatment.
Depending upon age and the type of mood disorder present, a person may exhibit different symptoms of depression. The following are the most common symptoms of a mood disorder; however, each individual may experience symptoms differently. Symptoms may include: persistent feelings of sadness; feeling hopeless or helpless; having low self-esteem; feeling inadequate; excessive guilt; feelings of wanting to die; loss of interest in usual activities or activities once enjoyed; difficulty with relationships; sleep disturbances; changes in appetite or weight; decreased energy; difficulty concentrating; a decrease in the ability to make decisions; suicidal thoughts or attempts; frequent physical complaints (i.e., headache, stomach ache, fatigue); running away or threats of running away from home; hypersensitivity to failure or rejection; and irritability, hostility, or aggression. In mood disorders, these feelings appear more intense than what a person may normally feel from time to time, and these feelings tend to continue over a period of time or interfere with an individual's interest in family, friends, community, or work.
Various treatments are currently available for mood disorders. Examples of current treatments include antidepressant medications, psychotherapy, and family therapy. Three major types of medication are typically used to treat depression: tricyclics, selective serotonin re-uptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO inhibitors). All three classes of medications are known to have varying degrees of effectiveness from patient to patient. Moreover, all three classes of medications are known to cause varying, undesirable side effects. It is estimated that approximately 44 million Americans experience a mental disorder each year, and mental illnesses are among the most common conditions affecting health today. Accordingly, there remains a need in the art for further pharmaceutical compositions useful in the treatment of mood disorders, particularly depression.
Sleep disorder encompasses a broad range of conditions, including sleep apnea (brief periods while sleeping during which breathing stops), insomnia (which includes difficulty falling asleep or staying asleep, waking too early, or Sleep State Misperception), narcolepsy (an irresistible need to sleep, where sleep attacks lasting from about 30 seconds to about 30 minutes occur during waking hours), and restless leg syndrome (a discomfort in the legs, often sensed while trying to sleep, which can include crawling, tingling, or prickling sensation, that can be relieved by moving or stimulating the legs). Sleep disorders are often comorbid with other conditions, such as depression, fibromyalgia, and chronic fatigue syndrome.
Narcolepsy, in particular, is known to adversely affect an individual's ability to function in daily life. This condition may be classified under the broader term of hypersomnia, which encompasses additional sleep attack conditions, such as idiopathic hypersomnia, recurrent hypersomnia, and hypersomnia resulting from a medical condition. The “sleep attacks” common with narcolepsy can occur at any time, such as while working, carrying on a conversation, or even driving a car. The four classic symptoms of narcolepsy are excessive daytime sleepiness; cataplexy (sudden, brief episodes of muscle weakness or paralysis brought on by strong emotions such as laughter, anger, surprise, or anticipation); sleep paralysis (paralysis upon falling asleep or waking up); and hypnagogic hallucinations (vivid dreamlike images that occur at sleep onset). Disturbed nighttime sleep, including tossing and turning in bed, leg jerks, nightmares, and frequent awakenings, may also occur.
There is no known cure for narcolepsy, but some evidence suggests the condition may be linked to abnormalities in cerebral perfusion. See Joo et al., Neuroimage (2005), 28(2): p. 410-416, which is incorporated herein by reference. Excessive daytime sleepiness is typically treated with stimulant drugs, such as methylphenidate (e.g., RITALIN®), dextroamphetamine (e.g., DEXTROSTAT® or DEXEDRINE®), methamphetamine (DESOXYN®), pemoline (CYLERT®), mazindol (SANOREX®), as well as the “non-stimulant” stimulant modafinil (PROVIGIL®). Cataplexy and other REM-sleep symptoms are often treated with antidepressant medications, such as venlafaxine (EFFEXOR®), fluoxetine (PROZAC®), reboxetine (EDRONAX®), imipramine (TOFRANIL®), desipramine (NORPRAMIN® or PERTOFRAN®), protriptyline (TRIPTIL® or VIVACTIL®), and atomoxetine (STRATERRA®). At best, known medications reduce the symptoms, but do not eliminate them entirely. Moreover, such pharmaceutical treatments often have undesirable side effects. Thus, there remains a need in the art for further pharmaceutical compositions useful in the treatment of sleep disorders, particularly narcolepsy.
Insomnia is typically described as difficulty in initiating and/or maintaining sleep, but the term is sometimes used to indicate any and all stages and types of sleep loss. The condition described by the term insomnia can actually encompass multiple types of sleep loss. Sleep onset insomnia (also known as delayed sleep phase syndrome) is a disorder in which the major sleep episode is delayed in relation to the desired clock time of sleep that results in symptoms of sleep onset insomnia or difficulty in awakening at the desired time. Idiopathic insomnia is a long-term (often lifelong) inability to obtain adequate sleep that is presumably due to an abnormality of the neurological control of the sleep-wake system. In such conditions, the insomnia is long-standing, commonly beginning in early childhood, and sometimes existing since birth. Psychophysiological insomnia is a disorder of somatized tension (i.e., conversion of anxiety into physical symptoms) and learned sleep-preventing association that results in a complaint of insomnia and associated decreased functioning during wakefulness.
Treatment for insomnia can vary depending upon the particular patient's needs. Most medications for treating insomnia are sedatives (i.e., hypnotics) or other sleep-inducing drugs, such as muscle relaxers and CNS depressants. Over-the-counter sleep aids typically include antihistamines (e.g., diphenhydramine or doxylamine), which have the side effect of causing sleepiness. Examples of prescription sleep aids include zolpidem (AMBIEN®), zalepon (SONATA®), and eszopiclone (LUNESTA®). Such medications are generally prescribed (or suggested in relation to OTC drugs) for short term use only. In the absence of drug treatment, several methods for inducing sleep have also been suggested. Methods used for treatment include behavioral modification, following good sleep hygiene practices, and light therapy.
Attention deficit disorder is officially recognized by the American Psychiatric Association as Attention-Deficit/Hyperactivity Disorder, or AD/HD, although most lay people, and even some professionals, still use the separate terms Attention Deficit Disorder (ADD) or Attention Deficit Hyperactivity Disorder (ADHD). Many researchers believe AD/HD is properly divided into three subtypes according to the main features associated with the disorder: inattentiveness, impulsivity, and hyperactivity. The three subtypes are: AD/HD Predominantly Combined Type; AD/HD Predominantly Inattentive Type; and AD/HD Predominantly Hyperactive-Impulsive Type.
The three subtypes take into account that some patients with AD/HD have little or no trouble sitting still or inhibiting behavior, but may be predominantly inattentive and, as a result, have great difficulty getting or staying focused on a task or activity. Others with AD/HD may be able to pay attention to a task but lose focus because they may be predominantly hyperactive-impulsive and, thus, have trouble controlling impulse and activity. The most prevalent subtype is the Combined Type, and patients with this subtype have significant symptoms of all three characteristics
AD/HD is a neurobiologically-based developmental disability, but there is currently no known specific cause for the condition. Some evidence suggests that the disorder is genetically transmitted in many cases and results from a chemical imbalance or deficiency in certain neurotransmitters. Other evidence suggests that AD/HD is partially a result of hypoperfusion of specific regions of the brain (e.g., a result of low regional cerebral blood flow). See Lou, Henriksen, and Bruhn, Archives of Neurology (1984), 41(8), which is incorporated herein by reference. Professionals who diagnose AD/HD use the diagnostic criteria set forth by the American Psychiatric Association (1994) in the Diagnostic and Statistical Manual of Mental Disorders; the fourth edition of this manual, known as the DSM-IV, was released in May 1994. The criteria in the DSM-IV, and other essential diagnostic features, are the signs of AD/HD. The primary features associated with the disability are inattention, hyperactivity, and impulsivity.
A patient with AD/HD is usually described as having a short attention span and as being distractible, distractibility and inattentiveness being non-synonymous. Distractibility refers to the short attention span and the ease with which some patients can be pulled off-task. Attention, on the other hand, is a process that has different parts, including focus (picking something on which to pay attention), selection (picking something that needs attention at that moment), and sustaining (paying attention for as long as needed). Attention also includes resistance (avoiding things that remove attention from where it needs to be) and shifting (moving attention to something else when needed). Symptoms of inattention, as listed in the DSM-IV, include: often failing to give close attention to details or making careless mistakes in schoolwork, work, or other activities; often having difficulty sustaining attention in tasks or play activities; often not seeming to listen when spoken to directly; often not following through on instructions and failing to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions); often having difficulty organizing tasks and activities; often avoiding, disliking, or being reluctant to engage in tasks that require sustained mental effort (such as schoolwork or homework); often losing things necessary for tasks or activities (e.g., toys, school assignments, pencils, books, or tools); often being easily distracted by extraneous stimuli; and often being forgetful in daily activities.
Excessive activity is the most visible sign of AD/HD. Symptoms of hyperactivity, as listed in the DSM-IV, include: often fidgeting with hands or feet or squirming in seat; often leaving seat in classroom or in other situations in which remaining seated is expected; often running about or climbing excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness); often having difficulty playing or engaging in leisure activities quietly; often being “on the go” or often acting as if “driven by a motor;” and often talking excessively.
Impulsivity of patients with AD/HD typically encompasses acting before thinking, because they have difficulty waiting or delaying gratification. The impulsivity leads these patients to speak out of turn, interrupt others, and engage in what looks like risk-taking behavior. A child may run across the street without looking or climb to the top of very tall trees. Although such behavior is risky, the patient is not really a risk-taker but, rather, has great difficulty controlling impulse. Symptoms of impulsivity, as listed in the DSM-IV, include: often blurting out answers before questions have been completed; often having difficulty awaiting turn; and often interrupting or intruding on others.
Many medications are approved for use in the treatment of AD/HD; however, stimulants, such as methylphenidate (e.g., RITALIN®) and dextroamphetamine (e.g., DEXTROSTAT® or DEXEDRINE®), are generally recognized as being the most effective pharmaceutical treatment. Other pharmaceutical treatments include atomoxetine (STRATTERA®), bupropion (WELLBUTRIN®), and alpha-2-agonists, such as clonidine (CATAPRES®). AD/HD is most prevalent in children, and many parents find it undesirable to treat their children through administering stimulants. Moreover, there can be undesirable side effects, such as decreased appetite, insomnia, increased anxiety, and/or irritability. Accordingly, there remains a need in the art for further pharmaceutical compositions useful in the treatment of AD/HD.